Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease (affecting 1 in 30,000) that is attributed to loss-of-heterozygosity (LOH) of the NF2 gene. By far the most common manifestation of the disease is the development of schwannomas of the 8th cranial nerve. Although our understanding of the molecular mechanisms underlying NF2 has significantly improved over the past 2 decades, and a number of potential therapeutic targets have been identified, viable treatment options are still lacking for this disease. Current treatment options are temporary anti-symptomatic interventions that are limited to radiation and/or surgery and associated with severe morbidity. Clearly, there is an urgent need to develop therapeutic options for NF2 patients. Currently, one of the main obstacles towards the development of effective drug treatments for NF2 is the lack of appropriate animal models to enable pre-clinical testing of drug candidates. To overcome this, we propose to develop a GEMM (Genetically Engineered Mouse Model) of NF2 that accurately reflects the biology of schwannoma development in patients, to incorporate a transgenic reporter allele allowing the temporal evaluation of drug candidate efficacy in an accurate and consistent manner. Towards this goal we will employ a recently described NF2 GEMM in which both Nf2 alleles are inactivated in Schwann cell progenitors, by crossing Nf2 conditional knockout mice to transgenic mice carrying a Cre-recombinase allele driven by the Periostin promoter. These mice will then be crossed to a reporter strain we developed, in which a novel bioluminescence resonance energy transfer (BRET) reporter allele can be conditionally turned on by Cremediated recombination. This newly developed reporter overcomes limitations previously experienced in animal models, such as a requirement for externally provided excitation light and limited penetration due to tissue absorption, by using a fusion of enhanced GFP to an enhanced variant of luciferase. The intra-molecular BRET between these proteins generates the brightest bioluminescent signal known to date and improves spatiotemporal monitoring of small numbers of tumor cells using in vivo optical imaging. In the R21 phase we will develop and internally validate this new NF2 GEMM. In the R33 phase we will determine the predicitive validity of the GEMM by testing it with 2 drugs previously shown to elicit an anti-tumor response in transplantable models of NF2. This will permit us to follow tumor growth and response to treatment, over an extended time period, in a GEMM that closely reflects the human disease.